Effect of Theophylline on Sleep and Sleep-disordered Breathing in Patients with Chronic Obstructive Pulmonary Disease1 , 2
RICHARD B. BERRY, MARGARET M. DESA, JAMES R BRANUM, and RICHARD W. LIGHT
Introduction
T he effects of theophylline therapy on sleep-disordered breathing and sleep quality in patients with chronic obstructive pulmonary disease (COPO) are unknown. These patients frequently complain of disturbed sleep, dyspnea and cough during the night, and periods of arterial oxygen desaturation during sleep are not uncommon (1). A circadian increase in bronchial motor tone during the early morning hours existsin normal subjects, and this is often accentuated in patients with airway disease (2). At the same time the effects of short-acting bronchodilator medications taken at bedtime decrease during the night. Thus, it is not surprising that sleep may be interrupted with dyspnea or cough in the early morning hours. Sustained-action theophylline preparations are available that permit dosing intervals of 8 to 12 h or longer (3). Therefore, these long-acting bronchodilators could be especially useful during sleep. Unfortunately, theophylline also has central stimulatory effects that may disturb sleep (4, 5). Such stimulation could offset the benefits of bronchodilation on sleep quality. The only reported evaluation of the effect of theophylline on sleep in patients with COPO was published in abstract form by Fleetham and coworkers (6). This single-blind crossover study showed that theophylline increased the mean sleeping oxygen saturation and decreased the mean transcutaneous Pco, in a group of patients with COPO. However, the total sleep time and the minutes of rapid eye movement (REM) sleep were decreased, and the arousal frequency was increased on theophylline nights. The presence or absence of concurrent bronchodilator therapy was not specified. In addition, there was no significant improvement in the FEV 1 on the theophylline night. Several studies of the effect of theophylline on the sleep of asthmatic subjects
SUMMARY To Investigate the effect of theophylline on sleep and sleep-dlsordered breathing In patients with chronic obstructive pulmonary disease (COPD), we studied 12 male non hypercapnic subjects with a mean ± SEM age of 62.8 ± 2.5 yr and aFEV 1 of 1.36 ± 0.11 L using a randomized double-blind crossover protocol. Sustained-action theophylline (250 mg three times or four times a day) or placebo was administered for 2 days, and the alternate drug was administered on the following 2 days. Sleep studies were performed on Nights 2 and 4 with spirometry at 9:00P.M. and 7:00A.M. 1\vo puffs of metaproterenol or albuterol were administered at 10:00P.M. on both study nights. A theophylline level, drawn at bedtime (10:00 to 11:00P.M.), was 14.2 ± 0.78 J,1g/mlon theophylline nights and < 2 on placebo nights. The morning FEV1 was significantly better during theophylline administration (1.27 ± 0.12 versus 1.00 ± 0.11 L, P < 0.001). The mean arterial oxygen saturation (Sa02)and transcutaneous carbon dioxide pressure (PC02)were also better during NREM sleep on theophylline nights. Neither the mean Sa02 and transcutaneous PC02 during REM sleep nor the apnea plus hypopnea Index (events per hour of sleep) differed between placebo and theophylline nights. Theophylline administration did not Impair the amount or architecture of sleep as neither total sleep time nor the fraction of time spent In Stages 1, 2, and 3/4 and REM differed between the two regimens. The number of arousals per hour of sleep was slightly less on theophylline nights (19.9 ± 1.7 versus 24.9 ± 2.7, P < 0.05). We conclude that the addition of sustained action theophylline to Inhaled beta-agonist therapy Improved spllometry and the arterial oxygen saturation during NREM sleep without Impairing sleep quality In a group of patients with COPD. AM REV RESPIR DIS 1991; 143:245-250
havebeen published, with somewhat conflicting results. Rhind and coworkers (7) found that sustained-release choline theophyllinate worsened sleep quality even though it improved early morning airflow when compared with placebo (no concurrent inhaled beta-agonists) in a group of asthmatics. In contrast, Zwillich and coworkers (8) found that sustained-action theophylline improved the sleeping arterial oxygenation and the early morning FEV 1 more than a longacting inhaled beta-agonist (bitolerol) in a population of asthmatics without adverselyaffecting sleep quality. The differences in the findings from these studies could be due to differences in the study populations or study designs(theophylline versus placebo or inhaled beta-agonist). In any case, the effects of theophylline on sleep in patients with COPO deserves further study. Results of studies in asthmatics may not be applicable to patients with COPO who are usually older and have less reversibility in airflow obstruction. The patients in the preliminary study of Fleetham and coworkers
(6) did not have improved airflow with theophylline. However, at least in some groups of patients with COPD, theophylline does improve airflow limitation and dyspnea (9), and these benefits might offset the stimulatory effects of theophylline with respect to sleep quality. Furthermore, most patients with significant COPD are treated with inhaled betaagonists if not with theophylline. We therefore undertook a study to evaluate the effect on sleep and nocturnal gas exchange and spirometry when theophylline was added to inhaled beta-agonist therapy using a double-blind randomized crossover protocol. (Received in original form October 17, 1989 and in revised form June 25, 1990) 1 From the Pulmonary Section, Long Beach Veterans Administration Medical Center, Long Beach, and the University of California at Irvine, California. 2 Correspondence and requests for reprints should be addressed to Richard B. Berry, M.D., PulmonarySection 111P, Long Beach VAMedica1Center, 5901 East 7th Street, Long Beach, CA 90822.
245
246
Methods Twelvemale patients, all fulfilling American Thoracic Society criteria for chronic obstructive pulmonary disease (10),were studied. All patients had been using theophylline as part . of their standard medications. The project was approved by the Institutional Review Board of our hospital. Subjects were admitted to the hospital, and informed consent was obtained. They had ingested no theophylline on the day of admission before coming to the hospital. Either placebo (P) or theophylline (T) as 250 mg Slo-Phyllin gyrocaps (Rorer, Fort Washington, PA) contained in a large pink gelatin capsule was administered for 2 days either three or four times a day at 9:00 A.M., 1:00 P.M., 5:00 P.M., and 9:00 P.M. In some cases the first dose was delayed by 1 or 2 h because of the admission procedures. On the third and fourth study days, the alternate drug was administered. Sleep monitoring was performed on the second and fourth nights. The subjects were asked to restrict their intake of caffeine-containing beverages on Days 2 and 4 of the study. The patients' nontheophylline regular medications were continued in their usual doses except that on the sleep study nights no inhaled bronchodilator was administered from 6:00 P.M. until after spirometry was performed at 9:00 P.M. Spirometry was repeated at 7:00 A.M. after the sleep studies and before any other inhaled medication was administered. A Vitalograph spirometer (Vitalograph, Lanexa, KS) was used, and the best FEV. and FVC of three attempts wererecorded. At 10:00 P.M. on sleep study nights, patients received two puffs of their standard beta-agonist (albuterol or metaproterenol), and venous blood was drawn for a theophylline level at bedtime (10:30to 11:00P.M.) and at 7:00 A.M. after the sleep study. Sleep monitoring was performed using el~ troencephalographic (EEG: C4Al or C3A2), electrooculographic (EOG), and chin electromyographic (EMG) leads to detect the presence and stage of sleep (11). Airflow at the nose and mouth was detected by a triple thermistor (Somnitec, Van Nuys, CAl. Respiratory effort (chest and abdominal movement) was monitored by respiratory inductance plethysmography (RIP) using a Respigraph (NIMS, Miami Beach, FL). The outputs of the rib cage and abdominal bands were summed (Vsum). Changes in Vsum were calibrated using a single-position method and a rolling-seal spirometer to give an estimate . of tidal volume (12). Calibrations wererepeated until the mean percent difference in tidal volume by spirometer and RIP differed by 100/0 or less in the favored sleeping position of the subjects. Arterial oxygensaturation was continuously measured using an Ohmeda III pulse oximeter. An electrocardiographic lead was monitored. Transcutaneous Pe02 was measured using a Transend Cutaneous Gas system (SensorMedics, Anaheim, CAl. The unit was calibrated before each study as follows (13). The membrane surface of the elec-
BERRY, DESA, BRANUM, AND LIGHT
trode was heated to 43.50 C and calibrated against 100/0 CO 2 in nitrogen. The subject's skin was then cleansed with alcohol and dried. A drop of aqueous contact medium was applied to the electrode, which wasthen fastened to the skin of the subjects (abdomen) with a double-sided adhesive ring and allowed to stabilize at least 15min before measurements were performed. The above parameters were continuously recorded on a Grass 78-D 12 channel polygraph (Grass Instruments, Quincy, MA) using a paper speed of 10 mm/s. A sleep quality questionnaire was completed by subjects upon awakening. Subjects wereasked to grade each night of sleep on a scale of 1 to 10 with 1 being the worst sleep and 10 the best sleep they had experienced. They were also asked to note on which night they had improved symptomatology in the following categories: "more sleepy," "coughed less," "breathed better," and "woke up less." Arterial blood gases weredrawn on admission, and full pulmonary function was obtained including a single-breath diffusing capacity and lung volumes by plethysmography (Collins DSII and BP body box; Warren E. Collins, Braintree, MA). The prediction equations for normal values of pulmonary function of the Intermountain Thoracic Society were used (14).
subtracting the mean value over 15 min during wakefulnessat the beginning of each study night from the appropriate mean values during sleep. The pulse rate during sleep was determined by averaging the mean pulse rate of every fifth epoch of sleep. Comparisons between theophylline and placebo nights were analyzed by the analysis of variance for repeated measures (15)using the order of the theophylline night (lor 2) as a between subjects factor and treatment (theophylline versus placebo) as the repeated measure (within-subjects factor). In this manner the effect of order and the interactions between order and treatment were analyzed. The FEV., and FVC, and FEV./FVC at 9:00 P.M. and 7:00 A.M. were analyzed in a similar manner except that two repeated measures factors (time and treatment) wereconsidered. The results of the sleep questionnaire were analyzed by computing the proportion of subjects noting improved symptoms ("breathed better," etc.) on the theophylline and on the placebo nights. If a subject noted no difference, 0.5 was added to the numerator of each ratio. The proportions were compared using chi-square analysis. A p value < 0.05 was considered statistically significant, and results were expressed as the mean ± SEM unless otherwise stated.
Data Analysis Sleep was staged in 30-s epochs using standard criteria (11). Total sleep time (TST), sleep latency, and sleep-period time (SPT) were determined. Sleep-period time was defined as the time from the first epoch of sleep until the final awakening. The time spent in each sleep stage in minutes and as a percentage of SPT and TST was also calculated. An arousal was defined as an abrupt change of sleep stage associated with a change in the EEG such as increased alpha activity. An apnea was defined as absence in airflow at the nose and mouth for 10 s or more. A desaturation was defined as a decrease in saturation of 40/0 or greater from the preceding baseline. A hypopnea was defined as a decrease in airflow of 500/0 or greater from the baseline lasting 10s or more and associated with a desaturation. The apnea plus hypopnea index was defined as the number of apneas and hypopneas per hour of sleep. The mean arterial oxygensaturation in NREM and REM sleepwere determined by averaging the saturation for each epoch of sleep. This was done by averaging the saturation tracings on the polygraph paper every 3 s unless the saturation was changing rapidly in which case every 0.6 s was used. If a desaturation occurred in an epoch occurring after the respiratory event (apnea, etc.) with which it was associated, the desaturation was considered to belong to the stage of sleep in which the respiratory event occurred. The mean transcutaneous Pe02 for NREM and REM sleep were determined In a similar manner. The mean changes in Pe02 compared with the waking values during NREM and REM sleep were determined by
Results
The subject data including age, baseline pulmonary function, and arterial blood gas analysis are presented in table 1. The patients had moderate to severe obstructive ventilatory dysfunction. Nine of the 12 patients had a reduced single-breath diffusing capacity for carbon monoxide « 80070 of predicted). No patient retained CO 2 , and only three had awake hypox.emia defined as a P0 2 < .70 mm Hg, The mean ± SEM theophylline level at bedtime on theophylline nights was 14.2 ± 0.78 ug/ml at 11:00P.M. and 14.2 ± 1.1 at 7:00 A.M. (p = NS). On placebo nights the level was < 2 ug/ml (the lowest level reported in our laboratory). The FEV 1 and FVC were significantly greater on theophylline nights at both 9:00 P.M. and 7:00 A.M. (table 2). The mean FEV 1 and FVC at 7:00 A.M. were about 25 and 15070 greater on theophylline nights. The mean FEV l/FVC ratio did not differ on placebo and on theophylline nights as the ratio increased in some patients and decreased in others, reflecting the relative changes in FEV 1 and FVC. The values of the FEV 1 and FVC were significantly lower at 7:00 A.M. than at 9:00 P.M. on both theophylline and placebo nights, 'Thus, although theophylline did not prevent the early morning worsening of air.flow obstruction (the falls in the FEV 1 and FVC overnight were very similar on theophylline and on placebo nights), the
247
THEOPHYLLINE AND SLEEP IN COPD
TABLE 1 PATIENT CHARACTERISTICS AND BASELINE PULMONARY FUNCTION Patient No.
Age (yr)
1 2 3 4 5 6 7 8 9 10 11 12
64 53 59 67 68 67 63 64 73 67 41 67
Mean ± SEM
62.8 2.5
Weight (/bs)
FEV1 (L)
FEV 1 (0/0 pred)
67 68 68 72 72 70 68 66 71 64 68 70
158 175 240 179 291 222 230 164 200 180 130 148
1.24 1.54 1.45 1.45 1.07 0.90 1.53 1.54 2.24 1.1 0.80 1.45
37.6 42.0 41.2 38.7 28.7 25.5 44.7 48.3 64.1 37.9 20.2 41.0
59 54 60 38 48 39 61 46 59 49 46 42
48.5 64.8 89.8 32.3 49.4 86.4 84.7 60.8 78.4 44.0 40.8 39.4
104 94 105 127 91 109 120 119 83 103 81 87
182 137 190 249 147 196 229 177 93 196 131 92
7.45 7.46 7.42 7.46 7.38 7.41 7.41 7.41 7.41 7.43 7.35 7.35
38 44 36 38 41 39 35
84
68.7 0.70
193 13
1.36 0.11
39.2 3.3
50.1 2.4
59.9 6.0
102 4.4
168 14.4
7.41 0.01
37.8 1.3
77.3 3.0
Height (inches)
absolute values of the early morning FEV 1 and FVC were higher on the theophylline nights. No significant quantitative or qualitative differences in sleep quality were found between theophylline and placebo nights. TST was very similar in both regimens (figure 1) and did not differ significantly (p = NS). The fraction of time occupied by Stages 1, 2, 3/4, or REM sleep as a percent of TS'I' or SPT did not differ in the two regimens (figure 2). The amount of Stage wake after sleep onset (absolute time or as a percentage of SPT) also did not differ on theophylline and on placebo nights. Thus, theophylline did not appear to reduce the total amount of sleep or reduce the amount of REM sleep. The mean sleep latency (lights out to first sleep) was similar on theophylline and placebo nights (34.8 ± 8.7 versus 38.7 ± 11 min, p = NS). In addition, the sleep efficiency (TST/SPT x 100) was not different on theophylline (73.2 ± 2.30/0) or on placebo (77.1 ± 2.40/0) nights. Thus, although our subjects took longer to fall asleep and slept less efficiently than do normal subjects, these values are not atypical for elderly patients with COPD (16). There was no
FEV 1 DLeo (0/0 FVC) (0/0 pred)
TLC (0/0 pred)
Rv (0/0 pred)
significant interaction between the order of the theophylline night (lor 2) and the effect of the theophylline versus placebo condition on TST, sleep latency, or the amount of time spent in the various sleep stages as a percentage of TST and SPT. Thus, the order with which theophylline or placebo was administered did not affect differences between theophylline and the placebo conditions with respect to any of the sleep variables compared. The subjective sleep quality (sleep questionnaire) did not differ on theophylline (6.0 ± 0.75) and on placebo nights (5.8 ± 0.75) where 1 is the worst and 10the best sleep ever. The proportion of subjects preferring theophylline or placebo nights, respectively, in the following symptom categories was "more sleepy": 5.5/12 versus 6.5/12; "less cough": 6/12 versus 6/12; "breathed better": 7/12 versus 5/12; "woke up less": 7/12 versus 5/12. The ratios on theophylline and on placebo nights did not differ significantly in any of the categories. The mean arterial oxygen saturations and transcutaneous carbon dioxide pressures are displayed in figures 3 and 4, respectively. Transcutaneous carbon dioxide measurements were obtained in
500
TABLE 2
! :E
43
89 95 75 76 59 77 87 80 74 66 66
~
D.
UJ UJ
p=NS
..
400
UJ
Placebo
32 29 39 39
P0 2 (mmHg)
only 11 subjects because of technical difficulties. During NREM sleep the mean arterial oxygen saturation was slightly but significantly higher and the mean transcutaneous Pco, was slightly lower on theophylline nights (p < 0.05). The corresponding parameters did not differ significantly during REM sleep. The mean increase in transcutaneous Pco, (mean ± SEM) during NREM sleep (above the waking value) was also slightly higher on placebo nights (3.00 ± 0.54 mm Hg) than on theophylline nights (2.05 ± 0.28) (p = 0.03). The corresponding mean increases in Pco, during REM sleep above the waking value on theophylline and on placebo nights were not significantly different. When the improvement in the bedtime FEV 1 on theophylline nights was compared with improvements in the mean Sae, during NREM sleep by linear regression, no significant correlation was found (correlation coefficient = 0.26, p = 0.5). The apnea plus hypopnea index did not differ on theophylline versus placebo nights (2.6 ± 0.72 versus 3.2 ± 0.75 per/h of
FEV1 AND FVC BEFORE AND AFTER SLEEP STUDIES· Theophylline
Peo2 (mmHg)
pH
300
...
...J
FEV 1 9:00 P.M. FEV 1 7:00 A.M. FVC 9:00 P.M. FVC 7:00 A.M. For both the FEV1 and FVC Theophylline> placebo 9:00 P.M. > 7:00 A.M. Order or interactions * Values are mean ± SEM.
1.45 1.27 3.03 2.63
1.18 1.00 2.64 2.26
± 0.11 ± 0.12 ± 0.17 ± 0.17
± ± ± ±
0.09 0.11 0.13 0.14
en
...J
~ 200
....o
100 . l . - - - - - - r - - - - - - - - - - , - - -
p P
< 0.001 < 0.01 NS
THEOPHYLLINE
PLACEBO
Fig. 1. Total sleep time (minutes) for each subject on theophylline and on placebo nights. The mean values were similar and not significantly different.
248
BERRY, DESA, BRANUM, AND LIGHT
;
p = NS
p =N S
~
70
~
70
•
50
~
50
~
.,
Fig. 2. The mean values of the amount of lime spent in the different sleep stages as a percentage of total sleep time and sleep period time on theophylline (open bars) and on placebo nights (closed bars). The values were very similar and did not differ significantly.
w ~
w
;: o
~
;:
~
~
30
30
w ~
~
w
~ .L.-...LL------'.:.L----il' --"'"'-_- '#
10
O.L..LI . -...LL---'-''-LL----'''-2
3+ 4
REM
SL EEP S T A GE S
10 0
p ::N S
p
RICHARD B. BERRY, MARGARET M. DESA, JAMES R BRANUM, and RICHARD W. LIGHT
Introduction
T he effects of theophylline therapy on sleep-disordered breathing and sleep quality in patients with chronic obstructive pulmonary disease (COPO) are unknown. These patients frequently complain of disturbed sleep, dyspnea and cough during the night, and periods of arterial oxygen desaturation during sleep are not uncommon (1). A circadian increase in bronchial motor tone during the early morning hours existsin normal subjects, and this is often accentuated in patients with airway disease (2). At the same time the effects of short-acting bronchodilator medications taken at bedtime decrease during the night. Thus, it is not surprising that sleep may be interrupted with dyspnea or cough in the early morning hours. Sustained-action theophylline preparations are available that permit dosing intervals of 8 to 12 h or longer (3). Therefore, these long-acting bronchodilators could be especially useful during sleep. Unfortunately, theophylline also has central stimulatory effects that may disturb sleep (4, 5). Such stimulation could offset the benefits of bronchodilation on sleep quality. The only reported evaluation of the effect of theophylline on sleep in patients with COPO was published in abstract form by Fleetham and coworkers (6). This single-blind crossover study showed that theophylline increased the mean sleeping oxygen saturation and decreased the mean transcutaneous Pco, in a group of patients with COPO. However, the total sleep time and the minutes of rapid eye movement (REM) sleep were decreased, and the arousal frequency was increased on theophylline nights. The presence or absence of concurrent bronchodilator therapy was not specified. In addition, there was no significant improvement in the FEV 1 on the theophylline night. Several studies of the effect of theophylline on the sleep of asthmatic subjects
SUMMARY To Investigate the effect of theophylline on sleep and sleep-dlsordered breathing In patients with chronic obstructive pulmonary disease (COPD), we studied 12 male non hypercapnic subjects with a mean ± SEM age of 62.8 ± 2.5 yr and aFEV 1 of 1.36 ± 0.11 L using a randomized double-blind crossover protocol. Sustained-action theophylline (250 mg three times or four times a day) or placebo was administered for 2 days, and the alternate drug was administered on the following 2 days. Sleep studies were performed on Nights 2 and 4 with spirometry at 9:00P.M. and 7:00A.M. 1\vo puffs of metaproterenol or albuterol were administered at 10:00P.M. on both study nights. A theophylline level, drawn at bedtime (10:00 to 11:00P.M.), was 14.2 ± 0.78 J,1g/mlon theophylline nights and < 2 on placebo nights. The morning FEV1 was significantly better during theophylline administration (1.27 ± 0.12 versus 1.00 ± 0.11 L, P < 0.001). The mean arterial oxygen saturation (Sa02)and transcutaneous carbon dioxide pressure (PC02)were also better during NREM sleep on theophylline nights. Neither the mean Sa02 and transcutaneous PC02 during REM sleep nor the apnea plus hypopnea Index (events per hour of sleep) differed between placebo and theophylline nights. Theophylline administration did not Impair the amount or architecture of sleep as neither total sleep time nor the fraction of time spent In Stages 1, 2, and 3/4 and REM differed between the two regimens. The number of arousals per hour of sleep was slightly less on theophylline nights (19.9 ± 1.7 versus 24.9 ± 2.7, P < 0.05). We conclude that the addition of sustained action theophylline to Inhaled beta-agonist therapy Improved spllometry and the arterial oxygen saturation during NREM sleep without Impairing sleep quality In a group of patients with COPD. AM REV RESPIR DIS 1991; 143:245-250
havebeen published, with somewhat conflicting results. Rhind and coworkers (7) found that sustained-release choline theophyllinate worsened sleep quality even though it improved early morning airflow when compared with placebo (no concurrent inhaled beta-agonists) in a group of asthmatics. In contrast, Zwillich and coworkers (8) found that sustained-action theophylline improved the sleeping arterial oxygenation and the early morning FEV 1 more than a longacting inhaled beta-agonist (bitolerol) in a population of asthmatics without adverselyaffecting sleep quality. The differences in the findings from these studies could be due to differences in the study populations or study designs(theophylline versus placebo or inhaled beta-agonist). In any case, the effects of theophylline on sleep in patients with COPO deserves further study. Results of studies in asthmatics may not be applicable to patients with COPO who are usually older and have less reversibility in airflow obstruction. The patients in the preliminary study of Fleetham and coworkers
(6) did not have improved airflow with theophylline. However, at least in some groups of patients with COPD, theophylline does improve airflow limitation and dyspnea (9), and these benefits might offset the stimulatory effects of theophylline with respect to sleep quality. Furthermore, most patients with significant COPD are treated with inhaled betaagonists if not with theophylline. We therefore undertook a study to evaluate the effect on sleep and nocturnal gas exchange and spirometry when theophylline was added to inhaled beta-agonist therapy using a double-blind randomized crossover protocol. (Received in original form October 17, 1989 and in revised form June 25, 1990) 1 From the Pulmonary Section, Long Beach Veterans Administration Medical Center, Long Beach, and the University of California at Irvine, California. 2 Correspondence and requests for reprints should be addressed to Richard B. Berry, M.D., PulmonarySection 111P, Long Beach VAMedica1Center, 5901 East 7th Street, Long Beach, CA 90822.
245
246
Methods Twelvemale patients, all fulfilling American Thoracic Society criteria for chronic obstructive pulmonary disease (10),were studied. All patients had been using theophylline as part . of their standard medications. The project was approved by the Institutional Review Board of our hospital. Subjects were admitted to the hospital, and informed consent was obtained. They had ingested no theophylline on the day of admission before coming to the hospital. Either placebo (P) or theophylline (T) as 250 mg Slo-Phyllin gyrocaps (Rorer, Fort Washington, PA) contained in a large pink gelatin capsule was administered for 2 days either three or four times a day at 9:00 A.M., 1:00 P.M., 5:00 P.M., and 9:00 P.M. In some cases the first dose was delayed by 1 or 2 h because of the admission procedures. On the third and fourth study days, the alternate drug was administered. Sleep monitoring was performed on the second and fourth nights. The subjects were asked to restrict their intake of caffeine-containing beverages on Days 2 and 4 of the study. The patients' nontheophylline regular medications were continued in their usual doses except that on the sleep study nights no inhaled bronchodilator was administered from 6:00 P.M. until after spirometry was performed at 9:00 P.M. Spirometry was repeated at 7:00 A.M. after the sleep studies and before any other inhaled medication was administered. A Vitalograph spirometer (Vitalograph, Lanexa, KS) was used, and the best FEV. and FVC of three attempts wererecorded. At 10:00 P.M. on sleep study nights, patients received two puffs of their standard beta-agonist (albuterol or metaproterenol), and venous blood was drawn for a theophylline level at bedtime (10:30to 11:00P.M.) and at 7:00 A.M. after the sleep study. Sleep monitoring was performed using el~ troencephalographic (EEG: C4Al or C3A2), electrooculographic (EOG), and chin electromyographic (EMG) leads to detect the presence and stage of sleep (11). Airflow at the nose and mouth was detected by a triple thermistor (Somnitec, Van Nuys, CAl. Respiratory effort (chest and abdominal movement) was monitored by respiratory inductance plethysmography (RIP) using a Respigraph (NIMS, Miami Beach, FL). The outputs of the rib cage and abdominal bands were summed (Vsum). Changes in Vsum were calibrated using a single-position method and a rolling-seal spirometer to give an estimate . of tidal volume (12). Calibrations wererepeated until the mean percent difference in tidal volume by spirometer and RIP differed by 100/0 or less in the favored sleeping position of the subjects. Arterial oxygensaturation was continuously measured using an Ohmeda III pulse oximeter. An electrocardiographic lead was monitored. Transcutaneous Pe02 was measured using a Transend Cutaneous Gas system (SensorMedics, Anaheim, CAl. The unit was calibrated before each study as follows (13). The membrane surface of the elec-
BERRY, DESA, BRANUM, AND LIGHT
trode was heated to 43.50 C and calibrated against 100/0 CO 2 in nitrogen. The subject's skin was then cleansed with alcohol and dried. A drop of aqueous contact medium was applied to the electrode, which wasthen fastened to the skin of the subjects (abdomen) with a double-sided adhesive ring and allowed to stabilize at least 15min before measurements were performed. The above parameters were continuously recorded on a Grass 78-D 12 channel polygraph (Grass Instruments, Quincy, MA) using a paper speed of 10 mm/s. A sleep quality questionnaire was completed by subjects upon awakening. Subjects wereasked to grade each night of sleep on a scale of 1 to 10 with 1 being the worst sleep and 10 the best sleep they had experienced. They were also asked to note on which night they had improved symptomatology in the following categories: "more sleepy," "coughed less," "breathed better," and "woke up less." Arterial blood gases weredrawn on admission, and full pulmonary function was obtained including a single-breath diffusing capacity and lung volumes by plethysmography (Collins DSII and BP body box; Warren E. Collins, Braintree, MA). The prediction equations for normal values of pulmonary function of the Intermountain Thoracic Society were used (14).
subtracting the mean value over 15 min during wakefulnessat the beginning of each study night from the appropriate mean values during sleep. The pulse rate during sleep was determined by averaging the mean pulse rate of every fifth epoch of sleep. Comparisons between theophylline and placebo nights were analyzed by the analysis of variance for repeated measures (15)using the order of the theophylline night (lor 2) as a between subjects factor and treatment (theophylline versus placebo) as the repeated measure (within-subjects factor). In this manner the effect of order and the interactions between order and treatment were analyzed. The FEV., and FVC, and FEV./FVC at 9:00 P.M. and 7:00 A.M. were analyzed in a similar manner except that two repeated measures factors (time and treatment) wereconsidered. The results of the sleep questionnaire were analyzed by computing the proportion of subjects noting improved symptoms ("breathed better," etc.) on the theophylline and on the placebo nights. If a subject noted no difference, 0.5 was added to the numerator of each ratio. The proportions were compared using chi-square analysis. A p value < 0.05 was considered statistically significant, and results were expressed as the mean ± SEM unless otherwise stated.
Data Analysis Sleep was staged in 30-s epochs using standard criteria (11). Total sleep time (TST), sleep latency, and sleep-period time (SPT) were determined. Sleep-period time was defined as the time from the first epoch of sleep until the final awakening. The time spent in each sleep stage in minutes and as a percentage of SPT and TST was also calculated. An arousal was defined as an abrupt change of sleep stage associated with a change in the EEG such as increased alpha activity. An apnea was defined as absence in airflow at the nose and mouth for 10 s or more. A desaturation was defined as a decrease in saturation of 40/0 or greater from the preceding baseline. A hypopnea was defined as a decrease in airflow of 500/0 or greater from the baseline lasting 10s or more and associated with a desaturation. The apnea plus hypopnea index was defined as the number of apneas and hypopneas per hour of sleep. The mean arterial oxygensaturation in NREM and REM sleepwere determined by averaging the saturation for each epoch of sleep. This was done by averaging the saturation tracings on the polygraph paper every 3 s unless the saturation was changing rapidly in which case every 0.6 s was used. If a desaturation occurred in an epoch occurring after the respiratory event (apnea, etc.) with which it was associated, the desaturation was considered to belong to the stage of sleep in which the respiratory event occurred. The mean transcutaneous Pe02 for NREM and REM sleep were determined In a similar manner. The mean changes in Pe02 compared with the waking values during NREM and REM sleep were determined by
Results
The subject data including age, baseline pulmonary function, and arterial blood gas analysis are presented in table 1. The patients had moderate to severe obstructive ventilatory dysfunction. Nine of the 12 patients had a reduced single-breath diffusing capacity for carbon monoxide « 80070 of predicted). No patient retained CO 2 , and only three had awake hypox.emia defined as a P0 2 < .70 mm Hg, The mean ± SEM theophylline level at bedtime on theophylline nights was 14.2 ± 0.78 ug/ml at 11:00P.M. and 14.2 ± 1.1 at 7:00 A.M. (p = NS). On placebo nights the level was < 2 ug/ml (the lowest level reported in our laboratory). The FEV 1 and FVC were significantly greater on theophylline nights at both 9:00 P.M. and 7:00 A.M. (table 2). The mean FEV 1 and FVC at 7:00 A.M. were about 25 and 15070 greater on theophylline nights. The mean FEV l/FVC ratio did not differ on placebo and on theophylline nights as the ratio increased in some patients and decreased in others, reflecting the relative changes in FEV 1 and FVC. The values of the FEV 1 and FVC were significantly lower at 7:00 A.M. than at 9:00 P.M. on both theophylline and placebo nights, 'Thus, although theophylline did not prevent the early morning worsening of air.flow obstruction (the falls in the FEV 1 and FVC overnight were very similar on theophylline and on placebo nights), the
247
THEOPHYLLINE AND SLEEP IN COPD
TABLE 1 PATIENT CHARACTERISTICS AND BASELINE PULMONARY FUNCTION Patient No.
Age (yr)
1 2 3 4 5 6 7 8 9 10 11 12
64 53 59 67 68 67 63 64 73 67 41 67
Mean ± SEM
62.8 2.5
Weight (/bs)
FEV1 (L)
FEV 1 (0/0 pred)
67 68 68 72 72 70 68 66 71 64 68 70
158 175 240 179 291 222 230 164 200 180 130 148
1.24 1.54 1.45 1.45 1.07 0.90 1.53 1.54 2.24 1.1 0.80 1.45
37.6 42.0 41.2 38.7 28.7 25.5 44.7 48.3 64.1 37.9 20.2 41.0
59 54 60 38 48 39 61 46 59 49 46 42
48.5 64.8 89.8 32.3 49.4 86.4 84.7 60.8 78.4 44.0 40.8 39.4
104 94 105 127 91 109 120 119 83 103 81 87
182 137 190 249 147 196 229 177 93 196 131 92
7.45 7.46 7.42 7.46 7.38 7.41 7.41 7.41 7.41 7.43 7.35 7.35
38 44 36 38 41 39 35
84
68.7 0.70
193 13
1.36 0.11
39.2 3.3
50.1 2.4
59.9 6.0
102 4.4
168 14.4
7.41 0.01
37.8 1.3
77.3 3.0
Height (inches)
absolute values of the early morning FEV 1 and FVC were higher on the theophylline nights. No significant quantitative or qualitative differences in sleep quality were found between theophylline and placebo nights. TST was very similar in both regimens (figure 1) and did not differ significantly (p = NS). The fraction of time occupied by Stages 1, 2, 3/4, or REM sleep as a percent of TS'I' or SPT did not differ in the two regimens (figure 2). The amount of Stage wake after sleep onset (absolute time or as a percentage of SPT) also did not differ on theophylline and on placebo nights. Thus, theophylline did not appear to reduce the total amount of sleep or reduce the amount of REM sleep. The mean sleep latency (lights out to first sleep) was similar on theophylline and placebo nights (34.8 ± 8.7 versus 38.7 ± 11 min, p = NS). In addition, the sleep efficiency (TST/SPT x 100) was not different on theophylline (73.2 ± 2.30/0) or on placebo (77.1 ± 2.40/0) nights. Thus, although our subjects took longer to fall asleep and slept less efficiently than do normal subjects, these values are not atypical for elderly patients with COPD (16). There was no
FEV 1 DLeo (0/0 FVC) (0/0 pred)
TLC (0/0 pred)
Rv (0/0 pred)
significant interaction between the order of the theophylline night (lor 2) and the effect of the theophylline versus placebo condition on TST, sleep latency, or the amount of time spent in the various sleep stages as a percentage of TST and SPT. Thus, the order with which theophylline or placebo was administered did not affect differences between theophylline and the placebo conditions with respect to any of the sleep variables compared. The subjective sleep quality (sleep questionnaire) did not differ on theophylline (6.0 ± 0.75) and on placebo nights (5.8 ± 0.75) where 1 is the worst and 10the best sleep ever. The proportion of subjects preferring theophylline or placebo nights, respectively, in the following symptom categories was "more sleepy": 5.5/12 versus 6.5/12; "less cough": 6/12 versus 6/12; "breathed better": 7/12 versus 5/12; "woke up less": 7/12 versus 5/12. The ratios on theophylline and on placebo nights did not differ significantly in any of the categories. The mean arterial oxygen saturations and transcutaneous carbon dioxide pressures are displayed in figures 3 and 4, respectively. Transcutaneous carbon dioxide measurements were obtained in
500
TABLE 2
! :E
43
89 95 75 76 59 77 87 80 74 66 66
~
D.
UJ UJ
p=NS
..
400
UJ
Placebo
32 29 39 39
P0 2 (mmHg)
only 11 subjects because of technical difficulties. During NREM sleep the mean arterial oxygen saturation was slightly but significantly higher and the mean transcutaneous Pco, was slightly lower on theophylline nights (p < 0.05). The corresponding parameters did not differ significantly during REM sleep. The mean increase in transcutaneous Pco, (mean ± SEM) during NREM sleep (above the waking value) was also slightly higher on placebo nights (3.00 ± 0.54 mm Hg) than on theophylline nights (2.05 ± 0.28) (p = 0.03). The corresponding mean increases in Pco, during REM sleep above the waking value on theophylline and on placebo nights were not significantly different. When the improvement in the bedtime FEV 1 on theophylline nights was compared with improvements in the mean Sae, during NREM sleep by linear regression, no significant correlation was found (correlation coefficient = 0.26, p = 0.5). The apnea plus hypopnea index did not differ on theophylline versus placebo nights (2.6 ± 0.72 versus 3.2 ± 0.75 per/h of
FEV1 AND FVC BEFORE AND AFTER SLEEP STUDIES· Theophylline
Peo2 (mmHg)
pH
300
...
...J
FEV 1 9:00 P.M. FEV 1 7:00 A.M. FVC 9:00 P.M. FVC 7:00 A.M. For both the FEV1 and FVC Theophylline> placebo 9:00 P.M. > 7:00 A.M. Order or interactions * Values are mean ± SEM.
1.45 1.27 3.03 2.63
1.18 1.00 2.64 2.26
± 0.11 ± 0.12 ± 0.17 ± 0.17
± ± ± ±
0.09 0.11 0.13 0.14
en
...J
~ 200
....o
100 . l . - - - - - - r - - - - - - - - - - , - - -
p P
< 0.001 < 0.01 NS
THEOPHYLLINE
PLACEBO
Fig. 1. Total sleep time (minutes) for each subject on theophylline and on placebo nights. The mean values were similar and not significantly different.
248
BERRY, DESA, BRANUM, AND LIGHT
;
p = NS
p =N S
~
70
~
70
•
50
~
50
~
.,
Fig. 2. The mean values of the amount of lime spent in the different sleep stages as a percentage of total sleep time and sleep period time on theophylline (open bars) and on placebo nights (closed bars). The values were very similar and did not differ significantly.
w ~
w
;: o
~
;:
~
~
30
30
w ~
~
w
~ .L.-...LL------'.:.L----il' --"'"'-_- '#
10
O.L..LI . -...LL---'-''-LL----'''-2
3+ 4
REM
SL EEP S T A GE S
10 0
p ::N S
p
